The present invention includes a composition, method of making and method of using a novel C5-substituted carbapenem antibiotic of formula 1:

##STR00001## R.sup.1 is H or CH.sub.3 R.sup.2 is not H, and is CH.sub.3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including CCH.sub.2; R.sup.3 is H, CH.sub.3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and R.sup.4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or R.sup.4 is an SR.sup.a, where R.sup.a is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7; or R.sup.4 is a CH.sub.2OR.sup.b, where R.sup.b=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups.

The present invention includes a composition, method of making and method of using a novel C5-substituted carbapenem antibiotic of formula 1:

##STR00001## R.sup.1 is H or CH.sub.3 R.sup.2 is not H, and is CH.sub.3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including CCH.sub.2; R.sup.3 is H, CH.sub.3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and R.sup.4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or R.sup.4 is an SR.sup.a, where R.sup.a is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7; or R.sup.4 is a CH.sub.2OR.sup.b, where R.sup.b=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups.

The present invention includes a composition, method of making and method of using a novel C5-substituted carbapenem antibiotic of formula 1: ##STR00001## R.sup.1 is H or CH.sub.3 R.sup.2 is not H, and is CH.sub.3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including CCH.sub.2; R.sup.3 is H, CH.sub.3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and R.sup.4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or R.sup.4 is an SR.sup.a, where R.sup.a is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7; or R.sup.4 is a CH.sub.2OR.sup.b, where R.sup.b=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups.

The present invention includes a composition, method of making and method of using a novel C5-substituted carbapenem antibiotic of formula 1: ##STR00001## R.sup.1 is H or CH.sub.3 R.sup.2 is not H, and is CH.sub.3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including CCH.sub.2; R.sup.3 is H, CH.sub.3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and R.sup.4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or R.sup.4 is an SR.sup.a, where R.sup.a is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7; or R.sup.4 is a CH.sub.2OR.sup.b, where R.sup.b=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups.

New antimicrobials targeting L,D-transpeptidases, non-classical cysteine peptidases, have been developed and their unique chemical structures identified. Carbapenems and penems of the present invention are unique among -lactams as they acylate and inhibit L,D-transpeptidases, which likely results in their superior antimicrobial potency. These new antimicrobial agents can be used alone, or in combination with other classic antimicrobial agents that target D,D transpeptidases, when treating bacterial infections.

New antimicrobials targeting L,D-transpeptidases, non-classical cysteine peptidases, have been developed and their unique chemical structures identified. Carbapenems and penems of the present invention are unique among -lactams as they acylate and inhibit L,D-transpeptidases, which likely results in their superior antimicrobial potency. These new antimicrobial agents can be used alone, or in combination with other classic antimicrobial agents that target D,D transpeptidases, when treating bacterial infections.

The disclosure is directed to new crystalline tebipenem pivoxil salt forms, including a crystalline tebipenem pivoxil ethane sulfonate salt form (Form A), a crystalline tebipenem pivoxil ketoglutarate salt form (Form A), tebipenem pivoxil maleate salt forms (Form A and Form B), a tebipenem pivoxil malate salt form (Form A), a tebipenem pivoxil methane sulfonate salt form (Form B), a tebipenem pivoxil hydrobromide salt form (Form B), and a tebipenem pivoxil edisylate salt form (Form A). The disclosure also includes a composition, comprising a crystalline tebipenem pivoxil salt and a pharmaceutically acceptable carrier and further includes a method for treating an antibiotic resistant bacterial infection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a crystalline tebipenem pivoxil salt.

The disclosure is directed to new crystalline tebipenem pivoxil salt forms, including a crystalline tebipenem pivoxil ethane sulfonate salt form (Form A), a crystalline tebipenem pivoxil ketoglutarate salt form (Form A), tebipenem pivoxil maleate salt forms (Form A and Form B), a tebipenem pivoxil malate salt form (Form A), a tebipenem pivoxil methane sulfonate salt form (Form B), a tebipenem pivoxil hydrobromide salt form (Form B), and a tebipenem pivoxil edisylate salt form (Form A). The disclosure also includes a composition, comprising a crystalline tebipenem pivoxil salt and a pharmaceutically acceptable carrier and further includes a method for treating an antibiotic resistant bacterial infection, comprising administering to a patient in need of such treatment a therapeutically effective amount of a crystalline tebipenem pivoxil salt.

This invention describes an ICE inhibitor prodrug (I) having good bioavailability.

##STR00001##

Compound I is useful for treating IL-1 mediated diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory peritonitis, septic shock, pancreatitis, traumatic brain injury, organ transplant rejection, osteoarthritis, asthma, psoriasis, Alzheimer's disease, myocardial infarction, congestive heart failure, Huntington's disease, atherosclerosis, atopic dermatitis, leukemias and related disorders, myelodysplastic syndrome, uveitis or multiple myeloma.

This invention describes an ICE inhibitor prodrug (I) having good bioavailability.

##STR00001##

Compound I is useful for treating IL-1 mediated diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory peritonitis, septic shock, pancreatitis, traumatic brain injury, organ transplant rejection, osteoarthritis, asthma, psoriasis, Alzheimer's disease, myocardial infarction, congestive heart failure, Huntington's disease, atherosclerosis, atopic dermatitis, leukemias and related disorders, myelodysplastic syndrome, uveitis or multiple myeloma.